Project Summary To date there is no clear physiological event that is associated with the development of sporadic AD. However, reproductive hormones are known to be critical modulators of cognition and neuronal function. Their deregulation, particularly in women, is a significant physiological senescence milestone with a clear impact on cognition and AD development. Estrogen (E2) has been the focus of hormone-based therapies for cognition and AD, however, with the failure of hormone replacement therapy (HRT) to improve function and protect from AD development in elderly women, focus has expanded to others that become equally deregulated during aging; one such group of hormones are gonadotropins such as LH. To this end, we and others, both at a clinical and basic level, have shown that increased peripheral levels luteinizing hormone (LH) that result from loss of E2 during menopause are an important contributor of cognitive dysfunction in women and a potential risk factor for AD. For example, we have published data demonstrating that reducing levels of peripheral LH is as effective as HRT at improving OVX and AD related cognitive and spine density loss, even beyond the critical period of ET effectiveness. However, the mechanisms that underlie these effects are unknown. We have now determined that LH is endogenously produced in the brain and that their levels are inversely correlated to levels in the periphery. This suggests that endogenous LH could have a role in the modulation of cognition and spine formation/remodeling. This is supported by findings that peripheral LH reductions, increases brain LH and leads to activation of signaling cascades associated with LH receptor (LHR) signaling that drive both cognition associated signaling and spine remodeling. Therefore, the goal of this proposal is to determine the involvement of the LH system on cognitive and spine density loss associated reproductive senescence (menopause) and whether dysregulation of LHR signaling drives AD development. To address this we will determine whether direct LH administration ICV under conditions of low brain LH (ovariectomy (OVX) and AD) rescue OVX and AD associated cognitive and spine density loss in normal and the APP/PS1 mouse model (AIM1). Further, to address whether brain-derived LH or LHR are involved in regulating cognition, spine density and AD pathology we will knockdown LH and LHR in brain using the CRISPR/Cas9 system and AAV 2/9 delivery of sgRNA (AIM 2). Lastly, given that LHR activation of several cascades associated with cognition and neuronal plasticity (Gs & Gq) we will determine the involvement of such cascades in regulating neuronal plasticity and AD related pathology in vitro using primary neuronal culture of B6J and APP/PS1 under basal and LHR knockdown and under inhibition of specific cascades after LH treatment (AIM 3). Together, these aims will provide the first and critical step to understanding how LH regulates cognitive and neuronal function in health and disease.